Safe and effective treatment for pain remains a global unmet medical need, which in turn has contributed to the opioid crisis. The experience of pain varies from person to person, with some individuals relatively resilient to pain compared to others. Individual-to-individual variation in pain, while observed in the clinics, has not been accurately modeled in the laboratory nor has its mechanistic underpinnings carefully examined. This is partially because pain involves both detection by the peripheral nervous system and perception in the central nervous system, and may be modulated by many factors including genetic, epigenetic, environmental and social. Our studies thus far of blood relatives with inherited erythromelalgia (IEM) with varying degrees of pain despite carrying the same Nav1.7 mutation (S241T), have allowed us to identify modulatory gene variants/mutations expressed in sensory neurons using whole exome sequencing, and indict one specific gene, KCNQ2, and suggest three additional genes, as modulators of pain in these patients. There are undoubtedly additional molecules that influence DRG neuron firing and modulate pain. In this proposed work, we will capitalize on our unique platform of induced pluripotent stem cell technology, and access to additional families with IEM and varying inter-individual pain profiles, to identify modulatory genes that might be developed into targets for the development of new pain treatments.